Exome Sequencing Reveals a Phenotype Modifying Variant in ZNF528 in Primary Osteoporosis with a COL1A2 Deletion
ORIGINAL ARTICLE Exome Sequencing Reveals a Phenotype Modifying Variant in ZNF528 in Primary Osteoporosis With a COL1A2 Deletion Sini Skarp,1,2,3† Ji-Han Xia,2,4† Qin Zhang,2,4 Marika Löija,2,3 Alice Costantini,5 Lloyd W Ruddock,2 Outi Mäkitie,5,6,7,8,9 Gong-Hong Wei,2,4,10† and Minna Männikkö1,3† 1Infrastructure for Population Studies, Northern Finland Birth Cohorts, Faculty of Medicine, University of Oulu, Oulu, Finland 2Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland 3Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland 4Biocenter Oulu, University of Oulu, Oulu, Finland 5Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet/Stockholm, Stockholm, Sweden 6Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden 7Children’s Hospital and Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland 8Folkhälsan Research Center, Genetics Research Program, Helsinki, Finland 9Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland 10Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences and Zhongshan Hospital, Fudan University, Shanghai, China ABSTRACT We studied a family with severe primary osteoporosis carrying a heterozygous p.Arg8Phefs*14 deletion in COL1A2, leading to hap- loinsufficiency. Three affected individuals carried the mutation and presented nearly identical spinal fractures but lacked other typical features of either osteogenesis imperfecta or Ehlers-Danlos syndrome. Although mutations leading to haploinsufficiency in COL1A2 are rare, mutations in COL1A1 that lead to less protein typically result in a milder phenotype.
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